title: A Phase I study of intermittently dosed vorinostat in combination with bortezomib in patients with advanced solid tumors.
abstract: BACKGROUND
  Accumulating evidence shows evidence of efficacy with the combination of vorinostat and bortezomib in solid tumors. We previously examined a once-daily continuous dosing schedule of vorinostat in combination with bortezomib which was well tolerated in cycles 1 and 2; however, there was concern regarding the tolerability through multiple cycles. This study was conducted to evaluate an intermittent dosing schedule of vorinostat with bortezomib.
  
  
  METHODS
  Vorinostat was initially administered orally twice daily on days 1-14 with bortezomib IV on days 1, 4, 8, and 11 of a 21 day cycle. Two DLTs (elevated ALT and fatigue) were observed at dose level 1, thus the protocol was amended to administer vorinostat intermittently twice daily on days 1-4 and 8-11.
  
  
  RESULTS
  29 patients were enrolled; 13 men and 16 women. Common cancer types included sarcoma, pancreatic, colorectal, GIST, and breast. The most common Grade 3-4 toxicities at any dose level included thrombocytopenia, fatigue, increased ALT, elevated INR, and diarrhea. DLTs in the intermittent dosing scheduled included thrombocytopenia and fatigue. The Cmax and AUC for the intermittent dosing regimen were similar to those observed in the daily dosing. In this heavily pretreated population, stable disease was observed in patients with sarcoma, colorectal adenocarcinoma and GIST.
  
  
  CONCLUSIONS
  The MTD was established at vorinostat 300 mg BID on days 1-4 and 8-11 and bortezomib 1.3 mg/m(2) IV on days 1, 4, 8, and 11 of a 21 day cycle. Tolerability was not improved with the intermittent dosing schedule of vorinostat when compared to continuous dosing.
authors.affiliation: University of Wisconsin Carbone Cancer Center, 600 Highland Avenue, K4/530 CSC, Madison, WI, 53792, USA.
authors.forename: Dustin A
authors.initials: DA
authors.lastname: Deming
authors.forename: Jacob
authors.initials: J
authors.lastname: Ninan
authors.forename: Howard H
authors.initials: HH
authors.lastname: Bailey
authors.forename: Jill M
authors.initials: JM
authors.lastname: Kolesar
authors.forename: Jens
authors.initials: J
authors.lastname: Eickhoff
authors.forename: Joel M
authors.initials: JM
authors.lastname: Reid
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Ames
authors.forename: Renee M
authors.initials: RM
authors.lastname: McGovern
authors.forename: Dona
authors.initials: D
authors.lastname: Alberti
authors.forename: Rebecca
authors.initials: R
authors.lastname: Marnocha
authors.forename: Igor
authors.initials: I
authors.lastname: Espinoza-Delgado
authors.forename: John
authors.initials: J
authors.lastname: Wright
authors.forename: George
authors.initials: G
authors.lastname: Wilding
authors.forename: William R
authors.initials: WR
authors.lastname: Schelman
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001897:Boronic Acids / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000069286:Bortezomib; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000077337:Vorinostat
chemical_list: D001897:Boronic Acids; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D011719:Pyrazines; D000077337:Vorinostat; D000069286:Bortezomib